pp. 98-104 in Human Genome Research and Society
Proceedings of the Second International Bioethics Seminar in Fukui, 20-21 March, 1992.

Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.

Copyright 1992, Eubios Ethics Institute
All commercial rights reserved. The copyrights for the employees of the US Government, are subject to other copyright arrangements. This publication may be reproduced for limited educational or academic use, however please enquire with Eubios Ethics Institute.

Medical genetics, social issues, and the genome programme

Derrek F. Roberts,
Emeritus Professor, Dept. of Human Genetics, University of Newcastle upon Tyne, UNITED KINGDOM

The genome initiative, probably the most ambitious project in the whole history of biological science, has as its aims to map man's genes, to lay bare that infinite complexity of biological information that makes him human. As a result of the publicity attending a research programme of this magnitude, considerable public interest has been aroused. A very real part of that interest has taken the form of doubts and worries as to how the new knowledge will be utilised, and for what purposes. These worries are not new, and indeed have been voiced to varying degrees ever since knowledge of human genetics began to accumulate. But perhaps never before have they been voiced on such a scale. The discipline of clinical genetics which has emerged in the last few decades has continually encountered some of them, but by respecting the accepted ethics of medicine has been able to alleviate them. Extending the accepted dictum to mens sana in corpore sana in famalia sana, it has concentrated on applications of genetic knowledge in family and preventive medicine and by doing so it has avoided any suspicion of acting in the interest of society rather than the individual.

Relatively few of the public, or indeed of clinicians with the possible exception of paediatricians, are aware of how extensive is the load of genetic disease in man. This became increasingly clear to clinical geneticists, from the first recognition of inborn errors by Garrod (1902) until the listing in the first edition of McKusick's catalogue (1966) where there were 1487 disorders noted as inherited in Mendelian fashion, and in the 8th edition (1988) there were 4344. Surveys of morbidity and mortality showed the extent of their effect (Roberts et al. 1970, Stevenson 1959, Miller 1964, Hall et al. 1978, Childs et al. 1972). The relevance of this knowledge in preventive and family medicine provided a continually administered spur to further efforts, not only in research but also in the development in Britain and elsewhere of genetic services, and clinical genetics was recognised as a speciality in its own right. Not only do genetic disorders make an appreciable contribution to the morbidity and the mortality load of the community. A major consideration is that very few of the numerous conditions can be treated effectively. A few can be corrected surgically, a few can be ameliorated or controlled therapeutically, but none can be cured. Prevention is still the only real solution. And this, by contrast to most other branches of medicine, usually means considering not only the patient suffering from the disease, but also others in his family who do not, and potential patients not yet born. Clinical genetics faces a number of ethical, practical and other issues that few other specialities encounter.

Prenatal Diagnosis

Until fairly recently the only means of prevention was for those who knew of severe genetic disease in their family to refrain from having children. This was accepted by quite a number of responsible beings. The first real modern step forward came either the possibility of prenatal investigation and diagnosis, followed by termination of a pregnancy if the fetus proved to be affected, a step which depended on two factors. The first was social acceptance of termination of pregnancy. This became possible in Britain in 1967 with the passage in Parliament of the Abortion Act, though still today this remains under attack from various pressure groups, and in a number of countries abortion for whatever reason is not socially accepted. But besides the social issue, there was the technical advance necessary to visualise by fetoscopy, or to obtain tissue deriving from, fetuses for diagnosis. The latter came principally with the development of mid-trimester amniocentesis in the 1970s. More recently has come chorionic villus sampling, which is done earlier in pregnancy than amniocentesis and so overcomes some of the social objections in that the pregnancy termination can be carried out earlier. Both were dependent on the development of ultrasound techniques for controlling the procedure and this subsequently developed to such refinement as to replace fetoscopy for visual examination of parts of the fetus so that many structural malformations can be detected. Amniocentesis and chorionic villus sampling are expensive and time-consuming and so need to be restricted to the women at high risk of producing a child with a defect. The defects detected have principally been the chromosomal disorders, particularly mongolism. But amniocentesis showed that features of the fetus other than its karyotype could also be examined. It has been possible for many years now to examine biochemically the products of fetal excretion in the amniotic fluid, and to grow fetal cells to obtain material for biochemical examination. The most widespread use of the former in Britain has been for detection of neural tube defects in those women at highest risk, today of course, following the development of more delicate assay techniques, available on a population basis after a preliminary screen has been carried out by examination of the alpha-fetoprotein level in maternal serum. Examination of the fetal cell culture for biochemical defects, several hundred in number, has been restricted to those families at risk if a specific disorder, and it has not been possible to implement it on a population screening basis.

Now with the development of knowledge of the human genome, and the ability to make a direct examination of the fetal DNA, the range of disorders in which the birth of a defective child can be prevented has expanded enormously. But essentially DNA analysis still relates only to the Mendelian single gene disorders (though it can be used (expensively) for some specific chromosomal investigations), and it will be a long time yet before genetic knowledge advances sufficiently for DNA examination to be usefully applied to the more complex disorders. Few of the Mendelian disorders are sufficiently common to warrant screening on a population basis, and for some time to come, prenatal DNA investigation will need to be restricted to those members known to be at high risk in families in whom a particular disorder occurs, as for example in a recessive when both of parents have been identified as heterozygous carriers for it.

The development of amniocentesis for prenatal diagnosis raised many of the social issues that have appeared again with the genome initiative. Two groups of issues can be discerned concerning questions of (a) the diagnostic procedure, (b) the termination of the pregnancy. Should prenatal diagnosis of a condition be carried out at all, is treatment other than pregnancy termination is not possible? There are many who disapprove, whose views must be respected, but it is generally accepted by the majority of parents who are at high risk. Should prenatal diagnosis be restricted only to those who are at high risk of producing an affected fetus? Here a major consideration is economic. The scientific procedure is expensive, and no health service could accept the cost of screening on a population basis except in specific populations characterised by a high frequency of a particular disease. But equally important, amniocentesis and chorionic villus sampling to obtain the requisite fetal specimen both carry a surgical risk, admittedly small and varying from one obstetric unit to another , but a real one. The tenet of nil nocere would preclude it except where the risk of an affected fetus outweighs this surgical risk. But having accepted the cost and the risk, and with the fetal specimen available, should investigation extend to more than the single condition that prompted the investigation? Having taken the risk of an invasive procedure, should as many investigations as are practicable be carried out to exclude other easily diagnosable conditions, for example other numerical aberrations or structural anomalies in the fetal karyotype in a chromosome analysis primarily directed to searching for Down's syndrome. Here again is the real issue. If by using methods of DNA analysis, gene dosage studies, or in situ hybridisation it is possible to detect trisomy 21 without the need for cell culture, then the number of cases examined could be increased and an almost complete screening of the maternal population be carried out in conjunction with serum alpha-fetoprotein screening. By doing so one would miss some of the chromosomal abnormalities, even though the majority of them may be quite small, but nevertheless serious, that would be detected using conventional techniques. The social issue is whether to opt to screen a larger number of women for a single very common disorder or whether to examine more widely a smaller number of pregnancies.

Termination of Pregnancy

Attitudes to pregnancy termination vary from society to society, and from one country to another. Whether or not it should be permitted at all is influenced by religious and moral beliefs involving the sanctity of human life at any stage. Clearly it would not be recommended for a relatively minor defect, and here what appears minor to one person may be totally unacceptable to another. An important factor then is the severity of the condition, and of this the new knowledge of the DNA variation responsible for particular conditions cannot yet give any indication - it can only indicate the presence of the gene responsible for the clinical condition this perhaps is one of the major problems still outstanding, how to distinguish degree of severity. A related consideration is the prospect of successful management of the disorder, successful not from the point of view of impartial clinical science, but from the point of view of the affected individual himself who is entitled to a good life. For very very few conditions do prospective parents understand what the future would involve, so it is not surprising to find that their attitude changes with time and experience.

From the scientific point of view, miscarriage is Nature's way of disposing of a defective fetus, as is shown by examination of the chromosomal constitution of abortuses at different stages of gestation. Human involvement in the decision implies concepts of defectiveness other than sheer survival which is the criterion which Nature employs. Here the human involvement is similar to (though the converse of) that later in life, when the patient without medical aid would die (Nature's way) but man uses his knowledge and skills to help that individual survive.

Such attitudes are relevant in the management of the responsible woman who opts for a termination of a pregnancy where the fetus is defective. Many today find it difficult to distinguish between the "genetic" termination, where the mother may in fact want the child but realises the difficulties that it would face in later life, from a "social" termination where the baby is not wanted. Certainly in the early days of screening for Down's syndrome among older mothers, it was by no means unusual for the woman to be admitted to an obstetric ward where she was surrounded by a majority of younger mothers, and she experienced unsympathetic attitudes not only from these but also from the staff as well. Her distress was enhanced by seeing the mothers in the ward with their new babies. The patient care after termination of pregnancy often still leaves much to be desired. In Britain, whereas a woman who loses her baby in the perinatal period has statutory health service support, the woman who has a genetic termination does not yet her grief reaction, her feelings, are no different. A follow-up study of such women shows the persistence of distress, their protracted depression (Laurence 1991), and it is clear that provision of postnatal diagnosis and termination of pregnancy, then follow-up support must be seen as an essential ingredient of it.

Investigation of Healthy Subjects

Application of prenatal diagnosis for recessive conditions, as distinct from other high risk situations, implies that the carrier status of both parents, themselves healthy, is established. Similarly for a severe dominant disorder of variable expression, reduced penetrance, or late onset, it may be necessary to investigate an apparently healthy individual to see if he is carrying the gene. Should such investigation be carried out at all if there is no cure? Should it be carried out in a child? Who should be responsible for instigating it? Who should be responsible for the findings, and for deciding to whom the knowledge should be reported? Such information may become available as a result of investigations of some other family members, for example a prenatal or presymptomatic diagnosis of a dominant in a child indicates that the parent through whom the gene has been transmitted is at risk of the disorder. Should such information be made available to him, and if so when? There is a great difference between knowing that one is at risk of developing a condition and knowing that one will develop it. Most individuals can live with a possibility, but they find it difficult to live with certainty - witness the number of suicides of patients in who Huntington's chorea has been diagnosed but before its development has progressed to an extreme stage. many of the problem,s become relevant when the individual is considering marriage or a family. In some cases information may need to be given earlier. For example in retinitis pigmentosa it may be important to make that knowledge available while a child is still in his teens, on account of the age at which he has to decide on his career. If he has set his mind on becoming an airline pilot, then there is a major educational decision to make, for he will not be able to follow that career if he is going to develop the eye disorder, and his hopes need to be directed along other channels. One should not be concerned only with testing, but also with the reasons why one is carrying out the tests. For carrier status of most recessive conditions, problems do not arise because the carrier suffers little if any adverse effect and it is only when marriage or reproduction is considered that the knowledge must be imparted. The same holds true for X-linked disorders, though in a number of these the female heterozygote experiences some effects, for example in Fabry's disease.

Confidentiality

Disclosure of a positive result of a presymptomatic diagnosis to the patient himself thus brings its own problems, rarely encountered in these age groups in other branches of medicine though more often at older ages. Perhaps there is only one situation in which it is essential, and that is when the patient is considering marriage or having a family, so that he is in full knowledge of the facts and can make an informed decision. A related situation is when his son or daughter and spouse are about to embark on having a family, where knowledge of the parental state may affect their decision. In all other cases disclosure needs to be considered on its merits.

Similar difficulties arise in regard to passing on that positive information to others. Even simple procedures that are routine in normal medical practice, such as reporting results of investigations in writing to family doctors, can create difficulties when the condition is serious. For such letters and reports on a desk or in a file may be seen by secretaries or filing clerks, or indeed other patients, so information may be inadvertently disseminated. The subject may wish to take out an insurance policy. It is usual for insurance companies to write to family doctors before issuing a policy, and if a family history of a severe inherited disorder is disclosed, most insurance companies will not accept the risk. A similar situation may apply to the granting of a mortgage, if the subject wishes to purchase a house, and it is by no means unusual that a mortgage application is turned down if there is a family history of a severe inherited disorder. Such problems are very real even without presymptomatic tests, and now that these have eliminated the element of doubt, the question is no longer one of risk but of certainty. There is a strong feeling that such information should not be disclosed to the insurance or mortgage companies, and indeed in Scandinavia it is now illegal to transmit genetic information this way. Thus unthinking disclosure may result in gross stigmatisation and discrimination against the unfortunate patient for both rational and irrational reasons. But there are times when the doctor cannot avoid a real ethical dilemma, for example if he knows that a patient in the course of his employment is in such a position that he may become a danger to others the patient can be advised to change his employment but he may refuse to do so, and the doctor then has to consider the wider implications of not disclosing that information to the employers. With the development of computer storage on patients, and of genetic registers, clearly the need to maintain confidentiality is critical and the system requires strict safeguards and limited access.

Discussion

The range of ethical and social issues associated with recent developments in knowledge of human molecular genetics is wide. Yet the applications of the new knowledge are essentially an extension of the preceding practice. For years Wassermann tests have been carried out in routine management of pregnancy, to warn of possible miscarriage or to prevent congenital syphilis in the infant. ABO and rhesus blood grouping have been standard procedures to establish whether or not there is materno-fetal incompatibility, and in the last few decades as a preliminary to negating possible rhesus sensitisation in the mother by the use of anti-D at the time of delivery if required. There is no real difference in these two procedures, except that one deals with an infectious condition, and the other with a genetic.

Both are however aimed at treatment. The apparently new problem of treatment by destruction when an untreatable and severe genetic condition is discovered prenatally, likewise was encountered in the genetic context some twenty years ago. Before that termination of pregnancy was always an option in cases of obstetric difficulties, where the life and health of the mother were the critical consideration. At a later developmental stage, a similar option faced the paediatrician confronted with a grossly malformed neonate who could decide not to purse resuscitation. It is however important not to lose a sense of perspective. The number of cases where such options were applied have always been very few and, of all pregnancy terminations, those carried out for genetic reasons form a small minority and are likely to remain such.

Many ethical and social issues attaching to screening have also been faced. At the population level, the implementation of the Guthrie screening test for phenylketonuria raised the numerous questions of informed consent, the understanding of the parents, the worry that was caused when a first positive result was encounters, how to impart that knowledge to the parents. Here prevention of development of the full disorder was possible. Similar issues arose in other situations where treatment was not possible, only termination. Examples are the introduction of screening for neural tube disorders by examination of alpha-fetoprotein level in maternal serum in Britain, which different health authorities resolved by adopting full screening, or opting out or opting in procedures, or not doing anything the implementation of the screening for Tay Sachs disease in the Jewish populations of the eastern United States where this was at high frequency, and of thalassaemia in some Mediterranean populations, where the carrier parents had previously been identified by screening procedures. Similar issues are currently being faced in the discussions of the introduction of cystic fibrosis screening in Britain, where it is the commonest of the recessive disorders.

The extent of understanding by the parents in all these cases is critical, so perhaps broadening of general education to cover these aspects of family building is required. But here it is essential that broader knowledge and acceptance of these procedures should not lead to stigmatisation of those parents who decide to continue a pregnancy where the fetus is affected.

It is clear then that these issues are not really new. What is new is the extent of what is now possible, the number of conditions detectable and the change from risk to certainty. Top undertake a fraction of the work to deal with all the relevant disorders would make enormous financial demands on the health services. So far this can be justified in terms of avoiding the cost of later management of affected individuals, and for a patient in an institution requiring lifelong care the amount is cast. Should society return to the system whereby such patients are cared for in the family? The attempt to do this for many longterm patients in mental institutions in Britain has not been a success. Here it is clear that family members must be available to provide the care, and therefore there must be a change from the present pressures for all to be occupied for financial gain outside the family. It would be an interesting paradox if the benefits of modern science could only be realised by a return to a more conservative way of life. The final question perhaps is the justification of such expenditure. Could the finance not be better employed alleviating the many other pressing problems of other societies, coping with infection, malnutrition, and the provision of even skeleton health services for the many millions for who they barely exist. Those countries where the applications of DNA procedures are feasible have conquered the gross problems of the morbidity and mortality patterns of earlier centuries, the quantitative burden of disease. The new knowledge is concerned with the quality of life, for the individual and for the family. Perhaps it is not too much to hope that this consideration will in time be relevant in those other developing countries who will then be able to profit from our experiences.